A growing body of evidence suggests that the gastrointestinal tract may play a significant role in the establishment of the immune response. This evidence includes: 1) A total lack of B cells in infants born without a terminal ileum, cecum and proximal colon, 2) Ly-1 immunoregulatory B cells are derived from an abdominal (not bone marrow) source, 3) there is precocius development of lymphoma in the gastrointestinal tract in several disease states (including XLP, nonpolyposis coli and coeliac disease), and 4) patients with Crohn's disease (which may have an autoimmune component) have a lower incidence of recurrance after extensive intestinal resection. The Ly-1 B cell has been linked to the production of autoantibodies in autoimmune mice, and is found in the highest frequency in autoimmune animals. Recent evidence has linked proximal colonic lymphoid tissue (PCLT) to Ly-1 B cells and autoimmunity, and has suggested that this tissue may be a site of primary lymphocyte differentiation. Therefore, it is the goal of this proposal to test the hypothesis that PCLT differs from other gastrointestinal lymphoid tissues, and that it may be a primary lymphopoietic organ (possiubly the source of a specialized subset of immunoregulatory B cells). The experiments in this proposal are designed to 1) investigate the ontogeny of PCLT, 2) characterize the lymphoctye and accessory cell subsets within PCLT, including their proliferative potential and migratory patterns, 3) evaluate strain differences in normal and immunodeficient/ immunodefective animals, 4) characterize the radiosensitivity of PCLT, 5) investigate the effects of oral/luminal antigenic challenge on PCLT, 6) determine whether PCLT can act as a source of B cell progenitors, and what types of cell populations are capable of reconstituting PCLT in irradiated individuals, 7) examine the effects of lymphokines on PCLT, and 8) determine whether proximal colectomy might cure autoimmune disease in animals whose autoimmune disease is associated with high levels of Ly-1 B cells. Completion of these experiments will allow a better understanding of the role of PCLT and other gastrointestinal lymphoid tissues in B cell differentiation and autoimmune disease states. Clearly proximal colonic lymphoid tissue has been a long neglected, yet perhaps ultimately critical part of the immunological status of an individual, and is worthy of further investigation.